Serotonin (5-hydroxytryptamine or 5-HT) is a monoaminergic neurotransmitter that has been implicated in embryonic development and in many physiological functions of the central nervous system, including sleep, appetite, aggression and sexual behavior. Serotonergic neurotransmission is involved in the etiology or treatment of many neuropsychiatric disorders, such as depression, schizophrenia, attention deficit hyperactivity disorder (ADHD), panic disorder, obsessive-compulsive disorder, social phobia, bipolar disorder, premenstrual syndrome or premenstrual dysphoric disorder (PMDD), bulimia nervosa and other eating disorders, autistic disorder, stroke, migraine, and nausea.
The serotonergic system is also the primary target for a number of drugs frequently used in psychiatry, such as tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase (MAO) inhibitors, anxiolytics (such as Buspirone), psychostimulants (such as cocaine), and hallucinogenic drugs (such as lysergic acid diethylamide (LSD) and (+)-3,4-methylenedioxyamphetamine (MDMA, “ecstasy”)). For example, drugs that enhance serotonin neurotransmission are commonly used in the treatment of depression, anxiety and other mood disorders.
Recent investigations of naturally-occurring genetic polymorphisms in humans and other species have identified mutations in the gene of the brain isoform of tryptophan hydroxylase (Tph2), a rate-limiting enzyme necessary for serotonin production, that lead to pronounced reductions in enzyme activity and serotonin synthesis. This enzyme catalyzes the conversion of the amino acid tryptophan to 5-hydroxytryptophan (5HTP), and this step is followed by decarboxylation of 5HTP by the L-aromatic amino acid decarboxylase to produce 5HT (serotonin).
Mice having a C1473G single nucleotide polymorphism (SNP) in Tph2 corresponding to a P447R mutation in the encoded protein showed a marked reduction in 5HT content in brain tissues (Zhang et al., 2004, Science 305:217). The expression of this Tph2 variant in specific inbred mouse lines is associated with reduced brain 5HT synthesis (Zhang et al., 2004, Science 305:217) and differences in aggressive behavior (Kulikov et al., 2005, Genes, Brain and Behav. 4:482-485), pre-mRNA editing of the 5HT2C receptor (Englander et al., 2005, J. Neurosci. 25:648-651), as well as responsiveness to SSRIs (Cervo et al., 2005, J. Neurosci. 25:8165-8172; Crowley et al., 2005, Psychopharmacol. (Berl.) 183:257-264). However, these studies compared different strains of inbred mice, and the potential contribution of other genetic variations in these mice cannot be ruled out.
A rare R441H Tph2 functional variant has also been identified in a small cohort of elderly patients with major unipolar depression (Zhang et al., 2005, Neuron 45:11-16). The R441H Tph2 mutations results in a reduction of hydroxylase activity by about 80% when expressed in a cell culture system. Large-scale genetic analyses have associated several non-coding polymorphisms in the human Tph2 gene with depression, bipolar disorder and suicidality (Harvey et al., 2004, Mol. Psychiatry 9:980-981; Zill et al., 2004, Mol. Psychiatry 9:1030-1036; Harvey et al., 2007, Psychiatr. Genet. 17:17-22; de Lara et al., 2007, Biol. Psychiatry 62:72-80; Lopez et al., 2007, Bio. Psychiatry 61:181-186). Naturally occurring functional polymorphisms in the Tph2 gene have also been identified in mice (Zhang et al., 2004, Science 305:217), rhesus monkeys (Chen et al., 2006, Mol. Psychiatry 11:914-928) and chimpanzees (Hong et al., 2007, Neurosci. Lett. 412:195-200).
Phenylalanine hydroxylase (PAH), an enzyme that is related to Tph2, also has a multiplicity of variants that lead to the development of human pathologies. For example, the PAH gene has 307 missense mutations have been reported to cause various degrees of phenylketonuria (Zhang et al., Cell Mol. Life Sci., 2006, 63: 6-11; Pey et al., 2003, 21: 370-378). This suggests that multiple functional Tph2 mutations may also exist in humans and potentially play a role in the etiology of mood disorders (See, e.g., U.S. Patent Application Publication No. 2006/0029951).